Modified factor VIII
AssigneeEmory University
InventorJohn S. Lollar
Life of this patent
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Abstract
Specific amino acid loci of human factor VIII interact with inhibitory antibodies of hemophilia patients who have developed such antibodies after being treated with factor VIII. Modified factor VIII is disclosed in which the amino acid sequence is changed by a substitution at one or more of the specific loci. The modified factor VIII is not inhibited by inhibitory antibodies against the A2 or C2 domain epitopes. The modified factor VIII is useful for hemophiliacs, either to avoid or prevent the action of inhibitory antibodies.
Claims6
A human factor VIII modified to comprise at least one amino acid substitution in the C2 domain wherein the substitution is limited to at least one position selected from the group consisting of 2181, 2182, 2195, 2196, 2197, 2207, 2216, 2222, 2224, 2225, 2226, 2228, 2234, 2238, and 2243 according to SEQ ID NO:
- 2, said substitution being insertion of an immunoreactivity-reducing amino acid for the naturally-occurring amino acid, wherein the immunoreactivity-reducing amino acid is selected from the group consisting of alanine, methionine, leucine, serine and glycine, said factor VIII having procoagulant activity.
A method for modifying human factor VIII such that reactivity to an inhibitory antibody is reduced and procoagulant activity is retained, comprising substituting an immunoreactivity-reducing amino acid for the naturally-occurring amino acid at at least one position in the C2 domain of human factor VIII, wherein the substitution is limited to at least one position selected from the group consisting of 2181, 2182, 2195, 2196, 2197, 2207, 2216, 2222, 2224, 2225, 2226, 2228, 2234, 2238, and 2243 according to SEQ ID NO:
- 2 and the immunoreactivity-reducing amino acid is selected from the group consisting of alanine, methionine, leucine, serine and glycine.
Dependencies are inferred from the claim text.